Appalachia is a socially and economically disadvantaged part of the US, and growing evidence suggests that health disparities between Appalachia and the rest of the country are widening. Gay, bisexual, and other men who have sex with men (GBMSM) and transgender women in rural Appalachia are at increased risk for HIV, sexually transmitted infections (STIs), and hepatitis C virus (HCV). There remains a dearth of effective approaches to address these emerging and intersecting epidemics among GBMSM and transgender women living in rural settings in the US. In Aim 1, our community-based participatory research (CBPR) partnership proposes to systematically integrate two evidenced-based strategies (i.e., peer navigation and mHealth) into a comprehensive culturally congruent, bilingual intervention to increase the use of needed HIV, STI, and HCV prevention and care services among racially/ethnically diverse GBMSM and transgender women in rural Appalachia. In Aim 2, we will implement and test the intervention through a longitudinal group-randomized design using behavioral assessment and in-depth interview data collected at: (1) baseline, (2) immediate post intervention, and (3) 12- month follow-up. Our hypotheses are that participants in the intervention group, relative to their counterparts in the delayed-intervention group, will demonstrate (1) increased HIV, STI, and HCV testing and (2) increased use of needed prevention services (PrEP and syringe services) and care services (HIV care, STI and HCV treatment, and gender-affirming care). In Aim 3, we will develop and disseminate practice, research, intervention, and policy priorities and recommendations to reduce health disparities in rural Appalachia by conducting an empowerment theory-based community forum. This CBPR study will advance prevention science and practice through testing an innovative intervention to promote and support the use of needed HIV, STI, and HCV prevention and care services among GBMSM and transgender women; and developing priorities and recommendations to improve their health that will be disseminated to inform public health practice, research, and policy. By integrating peer navigation and mHealth strategies, the proposed study provides a unique opportunity to improve health among vulnerable, hidden, and neglected populations living in rural Appalachia. Findings from this research may inform strategies and approaches to address other health disparities in other rural populations.